1. Field of the Invention
This invention relates to novel 3,4,5-trisubstituted aryl nitrone compounds and their use as therapeutic agents for the treatment of inflammation-related conditions in mammals, such as arthritis, and as analytical reagents for detecting free radicals.
2. State of the Art
Arthritis and related inflammatory disease conditions occur in more than 100 different forms, including rheumatoid arthritis (RA), osetoarthritis (OA), ankylosing spondylitis and systemic lupus erythematosus (SLE). Most forms of arthritis are charactgerized by some type of chronic inflammation. For example, RA typically involves chronic inflammation of the lining of the joints and/or the internal organs. Such chronic inflammation generally causes pain and swelling in the joints of those afflicted and may result in damage to cartilage, bone, tendons, ligaments and the like, ultimately leading to deformity and disability.
Prostaglandins have long been known to be involved in the inflammation process. Accordingly, a number of inhibitors of prostaglandin synthesis have been developed for the treatment of arthritis and related inflammatory disease conditions. Such non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen and indomethacin, typically prevent the production of prostaglandins by inhibiting enzymes in the arachidonic acid/prostaglandin pathway, including the enzyme cycloxygenase (COX). The enzyme COX catalyzes the conversion of arachidonic acid to prostaglandin H2, the first step in the biosynthesis of prostaglandins such as prostacyclin and thromboxanes. The enzyme COX is now known to exist in two forms. COX-1 is a constitutive form of the enzyme found in most tissues and organs. Among other properties, COX-1 produces relatively small amounts of prostoglandins necessary for maintaining the integrity of the gastrointestinal tract. COX-2, on the other hand, is an inducible form of the enzyme associated with the increased production of prostoglandins during inflammatory conditions. Since many NSAIDS inhibit both forms of COX, they interfere with prostaglandin-regulated processes not associated with the inflammation process. As a result, many NSAIDS cause severe side effects, such as stomach ulcers and renal damage, which limit their effectiveness as therapeutics.
The present invention employs certain members of the class of compounds known as nitrones. Nitrones have been used as pharmaceuticals and in other applications. See, for example, EP 0 945 426 A1 which shows one group of nitrones having 1 or 2 aromatic ring substituents; GB 2 137 619 which shows various nitrones as antiozonants in rubber; U.S. Pat. No. 5,025,032 which shows PBN and PBN derivatives useful in the treatment of stroke; WO 99 20601 which shows a aryl-N alkylnitrones having up to 3 ring substituents and their use as therapeutics for treating neurodegenerative, autoimmune and inflammatory conduction; WO 97/39751 which shows nitrones with up to 3 ring substituents including alkyls, alkoxies, aminoaryls, acyloxies, hydroxies, and carboxys; WO 95/11227 which shows various para hydroxy nitrones having two flanking alkyl substituents and their use in treating or preventing lipid peroxidation; and WO 91/05552 which teaches that PBN and a variety of PBN derivatives can be used to treat disorders associated with oxidative damage.
Accordingly, a need exists for novel classes of therapeutic compounds which effectively treat arthritis and other inflammation-related conditions without producing undesired side effects.